Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs

Tony L. Yaksh, Michael Rathbun, Juergen Jage, Todd Mirzai, Marjorie Grafe, Richard A. Hiles

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.

Original languageEnglish (US)
Pages (from-to)319-335
Number of pages17
JournalFundamental and Applied Toxicology
Volume23
Issue number3
DOIs
StatePublished - Oct 1994
Externally publishedYes

Fingerprint

Clonidine
Toxicology
Pharmacology
Dogs
Pathology
Toxicity
Spinal Cord
Foreign Body Giant Cells
Cerebrospinal fluid
Plasmas
Epidural Space
Clinical Pathology
Lymphocytes
Catheters
Blood pressure
Respiratory Rate
Body Temperature
Reaction Time
Cerebrospinal Fluid
Skin

ASJC Scopus subject areas

  • Toxicology

Cite this

Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. / Yaksh, Tony L.; Rathbun, Michael; Jage, Juergen; Mirzai, Todd; Grafe, Marjorie; Hiles, Richard A.

In: Fundamental and Applied Toxicology, Vol. 23, No. 3, 10.1994, p. 319-335.

Research output: Contribution to journalArticle

Yaksh, Tony L. ; Rathbun, Michael ; Jage, Juergen ; Mirzai, Todd ; Grafe, Marjorie ; Hiles, Richard A. / Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. In: Fundamental and Applied Toxicology. 1994 ; Vol. 23, No. 3. pp. 319-335.
@article{f0e6bbf9073c46f5bbb95d4f85bec51b,
title = "Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs",
abstract = "Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.",
author = "Yaksh, {Tony L.} and Michael Rathbun and Juergen Jage and Todd Mirzai and Marjorie Grafe and Hiles, {Richard A.}",
year = "1994",
month = "10",
doi = "10.1006/faat.1994.1112",
language = "English (US)",
volume = "23",
pages = "319--335",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs

AU - Yaksh, Tony L.

AU - Rathbun, Michael

AU - Jage, Juergen

AU - Mirzai, Todd

AU - Grafe, Marjorie

AU - Hiles, Richard A.

PY - 1994/10

Y1 - 1994/10

N2 - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.

AB - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.

UR - http://www.scopus.com/inward/record.url?scp=0027971457&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027971457&partnerID=8YFLogxK

U2 - 10.1006/faat.1994.1112

DO - 10.1006/faat.1994.1112

M3 - Article

VL - 23

SP - 319

EP - 335

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 3

ER -